This proposal describes a request for funds to purchase a Q-Exactive HF-X Hybrid Quadrupole-Orbitrap Mass Spectrometer with EASY-nLC 1200 System. The requested instrument is to upgrade the current proteomics capability in our facility with new features enabling identification of any known and unknown post-translational modifications (PTMs), label-free (MRM) and isobaric mass-labeled (TMT) protein quantitation, intact protein sequence analysis (top-down proteomics), and single amino acid polymorphism (SAAP) characterization over tissues and biopsies from healthy humans and patients with various diseases. Specifically, recent progress in Orbitrap-based mass spectrometry have dramatically increased the speed and accuracy of proteomics analysis, making it possible to determine the whole proteome of human tissues or cell lines with the highest accuracy and protein/peptide coverage. To take the advantage of the progress in hardware, new bioinformatic approaches, sophisticated algorithms, and big data clustering analysis have spontaneously emerged as new technologies to identify and quantify the whole proteomics for protein expression, isoform identification, unknown modifications and amino acid variations. These MS-based technologies have recently emerged to provide a high-throughput and in-depth proteomics platform for understanding the mechanisms of traumatic brain injury (TBI), Alzheimer disease (AD) and other neurodegenerative diseases in the elder veteran population. However, these new technologies are currently unavailable in our proteomics facility at VA Boston Healthcare System (VABHS) due to the outdated instrument for mass spectrometry. The present application describes our need for the requested instrument, its technical specifications, examples of how research can be furthered at VABHS through the use of this instrument, and a plan for its administration. In conclusion, the upgraded proteomics capability with the proposed instrument is urgently needed by our VA investigators and will be of particular importance in moving the discovery of VA-funded research into the next level of proteomics and uncovering the molecular mechanisms of VA-focused human diseases.